In this article, we present a novel method for the automatic 3D reconstruction of thick tissue blocks from 2D histological sections. The algorithm completes a high-content (multiscale, multifeature) imaging system for simultaneous morphological and molecular analysis of thick tissue samples. This computer-based system integrates image acquisition, annotation, registration, and three-dimensional reconstruction. We present an experimental validation of this tool using both synthetic and real data. In particular, we present the 3D reconstruction of an entire mouse mammary gland and demonstrate the integration of high-resolution molecular data.